Cancer, tumor-related disorders, and neoplastic disease states are serious and oftentimes life-threatening conditions. These diseases and disorders, which are characterized by rapidly-proliferating cell growth, continue to be the subject of research efforts directed toward the identification of therapeutic agents which are effective in the treatment thereof. Such agents prolong the survival of the patient, inhibit the rapidly-proliferating cell growth associated with the neoplasm, or effect a regression of the neoplasm. One class of cancer is leukemia which consists of malignancies derived from hematopoietic (blood-forming) cells. Part of this class of cancers is acute myeloid leukemia (AML), also known as acute myelogenous leukemia, which is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age.
In order to treat patients diagnosed with cancer, scientific researchers around the world have investigated a multitude of mutant cancer cells, genetic mutations, site-specific mutagenesis, DNA, RNA, RNA and protein expression, transporters, genetic sequencing, so as to map biochemical pathways in cancer cells at the molecular level and find the “cure” to various types of cancer and/or the ability to manage these as chronic diseases. One of the more recent cancer research fields consists of the investigation of the deregulation of the RNA metabolism that contributes to cells becoming cancerous, and even more specifically, the inhibition of a specific factor, eukaryotic translation initiation factor 4E (eIF4E), by a well-known anti-viral drug, ribavirin, which impedes eIF4E's ability to make cells cancerous without significantly affecting normal cells.
Ribavirin is chemically designated as: 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1 H-1,2,4-triazole-3-carboxamide, and has the following chemical structure:

The preparation of ribavirin is disclosed in U.S. Pat. No. 3,798,209. The clinical pharmacology of ribavirin is also disclosed in Glue, “The clinical pharmacology of ribavirin” Seminars in Liver Disease, vol. 19, suppl. 1, 1999, p. 17-24, 1999.
Canadian Patent Nos. 2,287,056 and 2,323,849 disclose an orally administrable solid dosage form containing a compacted ribavirin composition as well as a process for making such solid dosage forms.
A further discussion on the interaction of ribavirin with eIF4E can be found in: Assouline et al., “Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin” Blood, Vol. 114, no. 2 (2009); Borden, “Tissue Targeting in Cancer: eIF4E's Tale” Clin. Cancer Res., 2009); Borden et al., “Ribavirin targets eIF4E dependent Akt survival signalling”, Biochem. Biophys. Res. Commun., Vol. 375(3): 341-345 (Oct. 24, 2008); Kraljacic, et al., “Inhibition of eIF4E with ribavirin cooperates with common chemotherapies in primary acute myeloid leukemia specimens” Leukemia 25, 1197-1200 (July 2011) and other references known in prior art.
Canadian Patent Application No. 2,685,520 discloses compounds that are useful in treating viral infections and cancer, pharmaceutical compositions comprising the compounds, and synthetic methods and intermediates that are useful for preparing the compounds. The compounds that are useful as anti-viral agents and/or anti-cancer agents include ribavirin.
Canadian Patent Application No. 2,715,885 discloses novel compounds provided for use in the treatment of tumors and the prophylaxis or treatment of viral infections, wherein one of the anti-viral agents is ribavirin.
Canadian Patent Application No. 2,674,589 discloses compounds, as well as pharmaceutical compositions comprising the compounds that are useful as anti-viral agents and/or as anti-cancer agents, wherein the one of the anti-viral agents is ribavirin.
Canadian Patent Application No. 2,430,966 discloses anilinopyrimidine derivatives as JNK pathway inhibitors and compositions comprising administering an effective amount of an anti-cancer agent, wherein one of the proposed anti-cancer agents is ribavirin or cytarabine.
The eukaryotic translation factor, eIF4E, is found in all cells and is important to make new proteins. In cancer patients, the amount of eIF4E is overexpressed in AML, and is abnormally high in 30% of cancers, including the particularly aggressive subtypes of myeloid leukemia referred to as M4 and M5. The function of eIF4E to make new proteins depends upon its ability to bind to the front part of RNA known as the m7G cap (7-methyl guanosine) (located at the 5′ end of the mRNA), which then allows the cell to “translate” or turn this RNA into protein. It also has a role in the export of the mRNA into the cytoplasm, which must precede the translation step. It is known in the art that cancer cells with elevated levels of eIF4E seem to have developed an oncogene addiction to eIF4E.
Examples and reference can be seen in the prior art as follows: International laid-open publication nos. WO 2007/123579 and WO 2008/060369 (Translational Therapeutics); International laid-open publication no. 2010/006291 (Nodality Inc.), and U.S. Pat. Nos. 7,425,544 and 7,601,700 and International laid-open publication no. WO 2005/028628 (Eli Lilly and Co. and ISIS Pharmaceuticals Inc.), as well as Canadian Patent Application No. 2,632,903 (Nabil-Habib Lab and Vianova Labs Inc.) and some others.
Thus, because of its properties, the eukaryotic translation factor, eIF4E, has therefore become an appealing clinical target to treat patients diagnosed with cancer, in particular AML. In this connection, targeting of the eIF4E-m7G cap-binding activity has been studied in a phase II trial, in leukemia patients, and has been reported in Assouline et al., “Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin” Blood, Vol. 114, No. 2 (Jul. 9, 2009, Epub 2009 May 11). In this trial, the commonly used anti-viral drug, ribavirin, was found to decrease the function of eIF4E because it mimics the m7G cap; thus inhibiting eIF4E-induced export and translation of sensitive transcripts. In cell culture experiments, ribavirin did not modulate the levels of eIF4E protein or RNA. However in patients, ribavirin not only inhibits eIF4E, it also can lead to the downregulation of eIF4E protein (and RNA) levels as observed in patients in a phase II clinical trial using ribavirin monotherapy. Finally, in living cells, it was demonstrated that eIF4E binds 3H ribavirin further supporting the idea that eIF4E binds ribavirin directly in vitro and in vivo.
Several advantages have been disclosed in the prior art and from these disclosures, it can be understood that the physical mimicking of the natural ligand of eIF4E, ribavirin, preferentially inhibits the growth of primary AML (M4/M5 AML) specimens with elevated eIF4E levels relative to specimens with normal levels of eIF4E (e.g., M1/M2 AML) or normal controls. It is also taught that when ribavirin monotherapy is used, no treatment-related toxicities are observed. Further studies indicate that 3H ribavirin immunoprecipitates (IPs) with eIF4E in living cells further support the claim that ribavirin directly binds eIF4E.
In conducting clinical trial no. NCT00559091, the Applicant observed that many patients had resistance prior to the start of ribavirin therapy due to the other therapies they received or de novo. Also all responding patients became resistant to ribavirin monotherapy. In some patients, monotherapy had no impact suggesting that they were resistant prior to the start of treatment. Thus, a problem associated with a ribavirin monotherapy for use in cancer treatment, is that AML cells become resistant prior to the start of ribavirin therapy due to the other therapies or become resistant as a result of ribavirin treatment (primary versus acquired resistance, respectively).
In fact, leukemic cells become resistant to nearly all monotherapies within two (2) to four (4) months. To overcome this issue of resistance, it is not uncommon in the clinical field, and as for most treatments involving monotherapy, to combine such treatment, simultaneously or sequentially, with chemotherapy. The use of chemotherapeutic agents has many secondary effects on patients, including and not limited to damage of normal cells, anemia, bleeding, constipation, fatigue, hair loss, infections, memory changes, swelling, and even death, amongst many others. Conventional chemotherapy also requires a stay at the hospital so as to administer the chemotherapeutic agent(s) as well as supportive care for the side effects.
One of chemotherapeutic agents known for treating cancer is cytarabine, also known as Ara-C® (arabinofuranosyf cytidine or cytosine arabinoside), which is chemically designated as 4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl] pyrimidin-2-one. It has the following chemical formula:

Cytosine arabinoside is a chemotherapy antimetabolic agent used mainly in the treatment of cancers of white blood cells such as acute myeloid leukemia (AML) and non-Hodgkin lymphoma. It destroys cancer cells by interfering with DNA synthesis. Its mode of action is due to its rapid conversion into cytosine arabinoside triphosphate, which damages DNA when the cell cycle holds in the S phase (synthesis of DNA). Rapidly dividing cells, which require DNA replication for mitosis, are therefore most affected. Cytosine arabinoside also inhibits both DNA and RNA polymerases and nucleotide reductase enzymes needed for DNA synthesis.
Cytosine arabinoside combines a cytosine base with an arabinose sugar. Cytosine normally combines with a different sugar, deoxyribose, to form deoxycytidine, a component of DNA. Certain sponges, where it was originally found, use arabinoside sugars to form a different compound (not part of DNA). Cytosine arabinoside is similar enough to human cytosine deoxyribose (deoxycytidine) to be incorporated into human DNA, but different enough that it kills the cell. This mechanism is used to kill cancer cells. Cytarabine is the first of a series of cancer drugs that altered the sugar component of nucleosides.
Many combinations of drugs have been developed to treat patients diagnosed with cancer, including, for example, AML. For example, Zhu et al., “Novel agents and regime for acute myeloid leukemia: 2009 ASH annual meeting highlights” Journal of Hematology & Oncology 2010, 3:17 (Review) discloses monotherapies of daunorubicin, voreloxin, ARRY-520, AZD1152, AZD6244 and terameprocol, as well as combinations of drugs such as: cytarabine with daunorubicin; fludarabine, cytarabine with idarubicin, mitoxantrone with cytarabine; clofarabine alone or in combination with low-dose Ara-C® or high dose Ara-C® with the monoclonal antibody GO; combination therapy with sorafenib; tipifarnib with bortezomib; azacitidine with botezomib or low-dose GO; amonafile with Ara-C®; lenalidomine, Ara-C® and daunorubicin; as well as ribavirin with Ara-C®, in the treatment of elderly AML or relapsed AML or refractory AML.
The combination of ribavirin and low-dose Ara-C®, Ara-C® and idarubicin, and combinations thereof (i.e. ribavirin, Ara-C® and idarubicin) as well as sorafenib with ribavirin was specifically disclosed by Assouline et al. in “Targeting the oncogene eIF4E with ribavirin: a novel therapeutic avenue in acute myeloid leukemia” Blood 114, 2009 and by Kraljacic et al. in “Inhibition of eIF4E with ribavirin cooperates with common chemotherapies in primary acute myeloid leukemia specimens” Leukemia 25, (2011).
Clinical trials have also been conducted on several combinations of drugs for the treatment of leukemia and/or AML, and are available at: clinical trials.gov (NTC01056523) and http://clinicaltrials.gov/ct2/home.
Examples of combinations of therapy for AML, include and are not limited to: ABT-348; ABT-888 and topotecan with or without carboplatin; alemtuzumab, busulfan, and cyclophosphamide; alemtuzumab, busulfan, and melphalan; alemtuzumab with fludarabine phosphate; all-trans retinoic acid with bryostatin 1; amifostine trihydrate, cytarabine with mitoxantrone hydrochloride; arsenic trioxide; azacitidine with cytarabine (also referred to as Ara-C (Registered trademark)); azacitidine, asparaginase, cytarabine, aunorubicin hydrochloride, etoposide, lintuzumab with thioguanine; azacitidine with arsenic trioxide; azacitidine with belinostat; azacitidine with entinostat; azacitidine with gemtuzumab ozogamicin; azacitidine with lenalidomide; azacitidine with midostaurin; 5-azacytidine (Vidaza (Registered trademark)) with panobinostat (lbh589); 5-azacytidine (5-aza), valproic acid with all-trans retinoic acid (atra); azacytidine with valproic acid; azacitidine with phenyl butyrate; basiliximab; becatecarin; belinostat; bendamustine; bevacizumab, cytarabine with mitoxantrone hydrochloride; bexarotene and gm-csf; BMS-214662; bortezomib with belinostat; bortezomib with melphalan; bortezomib and vorinostat; bryostatin 1; busulfan, filgrastim with etoposide; busulfan with fludarabine; busulfan, cyclophosphamide, mycophenolate mofetil with tacrolimus; carboplatin, docetaxel with ifosfamide; cediranib maleate; clofarabine; clofarabine with cyclophosphamide; clofarabine, cytarabine with idarubicin; clofarabine, filgrastim with cytarabine; clofarabine and high-dose melphalan; clofarabine, melphalan, and thiotepa; cilengitide; cixutumumab with temsirolimus; CPX-151; CT53518; cytarabine and daunorubicin with or without gemtuzumab ozogamicin; cytarabine and daunorubicin with or without zosuquidar trihydrochloride; cytarabine, idarubicin with tipifarnib; cytarabine with 7-hydroxystaurosporine; cytarabine with laromustine; cytarabine with tanespimycin; cytarabine with triapine; cyclophosphamide; cyclosporine and Given IV with mycophenolate mofetil; cyclosporine, mycophenolate mofetil, and pentostatin; cyclosporine, methotrexate, methoxsalen, mycophenolate mofetil with pentostatin; decitabine; decitabine with lenalidomide; decitabine with romidepsin; decitabine with tretinoin; decitabine with valproic acid; decitabine with vorinostat (sequential); deferasirox; dolastatin; eltrombopag olamine; entinostat; everolimus; exatecan mesylate; fentanyl citrate; flavopiridol and vorinostat; fludarabine and cyclophosphamide as well as total-body irradiation, followed by cyclosporine and mycophenolate mofetil; fludarabine phosphate with Given IV; fludarabine phosphate with tretinoin; fludarabine, carboplatin, and topotecan; fludarabine, carboplatin, topotecan with thalidomide; fludarabine with melphalan; fludarabine with thiotepa; fludarabine with treosulfan; gimatecan; 7-hydroxystaurosporine with perifosine; hydroxyurea with laromustine; idarubicin with saha (vorinostat); ipilimumab; imatinib mesylate; interleukin-12 followed by interferon alfa; irofulven; itraconazole with midostaurin; ispinesib; JNJ-26481585; KW-2449; laromustine; lintuzumab; lonafarnib; MEK inhibitor AZD6244; MS-275 and gm-csf; MGCD0103; MLN8237; mycophenolate mofetil, tacrolimus with daclizumab; ON 0191 O.na; OX14503; palivizumab with or without ribavirin; paricalcitol; phenyl butyrate and tretinoin; procrit; pyroxamide; fluorouracil, leucovorin calcium, and topotecan hydrochloride; rasburicase; revlimid; romidepsin; sargramostim, amifostine trihydrate, carboplatin with cyclophosphamide; S81518; SJG-136; STA-9090; sirolimus with tacrolimus; sodium salicylate; sorafenib tosylate; sorafenib with vorinostat; tacrolimus and mycophenolate mofetil with or without sirolimus; tacrolimus and mycophenolate mofetil; tetradecanoylphorbol acetate; temsirolimus; tipifarnib; triapine with fludarabine phosphate; vorinostat; and yttrium y 90 anti-cd45 monoclonal antibody ahn-12, amongst others.
As noted in the prior art, the population having advanced AML had difficulty receiving more than one cycle of therapy. Anti-leukemia activity could be observed with relapsed/refractory disease. Another problem associated with AML drug therapies is epigenetic silencing; a phenomenon by which a drug-induced increased methylation allows for acquired drug resistance. The contribution of epigenetic mechanisms for correct cell function is highlighted by the effects of their deregulation that, in cooperation with genetic alterations, lead to the establishment and progression of tumors (see Fazi et al., in “Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia”, Blood, May 2007, vol. 109(10), p. 4432-4440).
Other problems with concomitant drug therapy is that the drugs may produce antagonistic effects, undergo collateral sensitivity/resistance to other drugs, be difficult to determine the right dosing regimen, have toxicity issues; and create multiple drug resistance. From the above, it becomes apparent that the treatment of myelodyplastic syndromes (MDS) and/or AML remains a challenge to the clinician despite recent advances. Many patients either will not respond or will have only limited and/or brief responses to single agent therapy or even concomitant therapy.
Even in the early stage of clinical trials, some side effects have been observed, which were due to low dose Ara-C®. Hemolysis has also been observed in a patient treated with the combination of ribavirin and Ara-C®. This phenomenon can be attributed to ribavirin, but such side effects were not observed in the ribavirin monotherapy trial (NCT NCT00559091). It is possible that Ara-C® somehow potentiates this side effect. No therapy related side effects were observed with ribavirin alone.
Most virus studies have primarily focused on the effects of ribavirin on the virus, for example: mutations in viral polymerases, which is not the case in the context of the present invention. In the viral context, ribavirin impedes growth of the virus and resistance occurs when the virus continues to replicate even in the presence of ribavirin. In the cancer context, it is a measure of cells becoming resistant to the anti-proliferative effects of ribavirin, i.e. that eIF4E mediates proliferation, ribavirin impedes this effect and then eventually, the cells continue to proliferate even in the presence of ribavirin. Further, there could be different biochemical pathways modulated. Thus, one cannot compare viral infections, such as the hepatitis C virus (HCV) or the poliovirus, with cancerous type cells or cell growth as the mechanisms of action and resistance are completely different.
Drug resistance is a major impediment in cancer research, particularly for SCLC because of limited recent innovations in treatment methods. One possible explanation for chemoresistance is activation of the hedgehog signaling pathway, which promotes cellular proliferation and differentiation and has been implicated in chemoresistance. Its gene expression was examined in resistant SCLC cell lines and reported aberrant expression of hedgehog pathway-related genes, among which GUI was particularly significant. GLI1 is a transcription factor involved in cell fate determination, proliferation, oncogenesis, and cancer progression.
With the use of new effective chemotherapy, hormone therapy, and biological agents and with information regarding more effective ways to integrate systemic therapy, surgery, and radiation therapy, elaborating an appropriate treatment plan is becoming more complex. To offer better treatment with increased efficacy and low toxicity, selecting therapies based on the patient and the clinical and molecular characteristics of the tumor is necessary.
Therefore, accordingly a need exists to overcome the aforementioned drawbacks by a combination therapy.